P882: IDENTIFICATION OF M7G RNA METHYLATION REGULATORS AND M7G-RELATED GENES IN MULTIPLE MYELOMA
Authors: M. Yu, C. Li, J. Xu, M. Liu, X. Cui
Journal: HemaSphere (2022)

Background: N7-methylguanosine (m7G) is a positively charged, essential modification at the 5’ cap of eukaryotic mRNA, impacting RNA processing and function, especially mRNA sublocation, translation, and splicing, which is crucial for the regulation of tumor progression. However, the m7G modification pattern of multiple myeloma (MM) is still unclear. Aims: To explore the impact of m7G regulators on MM prognosis and further conducted a comprehensive investigation on the differences in m7G-related genes among different m7G modification patterns. Methods: We analyzed the mRNA expression of m7G regulators in healthy donors (n = 9) and MM (n = 174) bone marrow plasma cells, investigated their prognostic values, and comprehensively evaluated the m7G modification patterns of 559 MM bone marrow samples. These data are from Gene Expression Omnibus (GEO) datasets. ConsensusClusterPlus R package (1.56.0) was used to group patients. Results: Compared with healthy donors, the expression of three m7G writers (METTL1, RNMT, and WBSCR22) was significantly upregulated in MM patients (Fig. 1A). The Kaplan-Meier (K-M) survival curve showed that three m7G regulators (METTL1, WDR4 and RNMT) were significantly correlated with survival, and their high expression was associated with shorter overall survival (OS) (Fig. 1B). Based on the expression levels of m7G regulators, MM patients with qualitatively distinct m7G modification patterns were classified into three different groups. The K-M curve analysis showed a significant survival difference among the subgroups, of which cluster A showed a worse outcome than clusters B and C (Fig. 1C), and the expression of m7G regulators was higher in cluster A (Fig. 1D). To further investigate the biological behaviors of these distinct m7G modification patterns, gene set variation analysis (GSVA) was performed. Compared with clusters B and C, cluster A was markedly enriched in cell proliferation-related pathways. Recent studies have found that the m7G cap in eukaryotic mRNAs is necessary to regulate sublocation, translation, and splicing. Therefore, we used the Pearson correlation coefficient to determine the potential m7G-related mRNAs. As a result, 88 interactions and 88 m7G-related mRNAs (absolute correlation coefficient >0.3, P <0.05) were identified. Further univariate Cox analysis revealed that 27 mRNAs were independent prognostic factors for MM patients, 20 of which were high-risk genes, with varying expression levels in each group (Fig. 1E and 1F). Among them, CDK4, a high-risk gene highly expressed in cluster A (Fig. 1G), is closely associated with cell proliferation by regulating the cell cycle, which is consistent with the GSVA results. As with other cancers, cell cycle dysregulation leads to the progression of MM, where CDK4/6 disorders are common. Image:Summary/Conclusion: This work showed that the high expression of m7G regulators was correlated with unfavorable prognostic outcomes in MM. The difference in m7G modification patterns may be an important factor in determining the prognosis of MM patients via causing disorders of the cell cycle.